The change in the product portfolio of many chemical companies away from commodities to customer-specific specialties is one of the current challenges facing the process industry. Flow chemistry or milli- and ­micro reaction technology (MRT) is a technology platform that can offer enormous advantages in this respect.

What is the state of the art, the dissemination and acceptance as well as the requirements for further establishment of the flow chemistry technology in the chemical and pharmaceutical industry? CHEManager had invited to the roundtable “Flow Chem­istry”, Dechema, the German expert network for chemical engineering and biotechnology, provided the appro­priate framework, and many experts came to discuss these questions.
MRT replaces the discontinuous batch process with a continuous process in which reactions take place in structures with a drastically reduced size. The main components are mixers with excellent mixing speed and heat exchangers with high heat transfer capacities. This results in improved process control and sig­nificant miniaturization of reactive volumes. The excellent mixing and temperature control with hardly measurable temperature gradients over the whole reaction volume cannot be achieved in a classical batch reactor. Due to the exact controllability of the reaction process, the reaction parameters can be better adjusted, resulting in higher product purity and better yields. The small volumes in milli and micro reactors allow the physical process conditions to be extended to higher or lower temperatures or pressures while maintaining a safe and fully controlled unit.

Safety and Process Control
The main advantages of continuous operation in micro and milli reactors are thus ultra-fast mixing, highly efficient heat transfer, simple process control due to low system inertia and high operational safety due to minimal hold-up. These properties of continuous flow reactors are particularly advantageous for fast, highly exothermic reactions with explosive or toxic substances; due to the high ­safety risk, these processes are often difficult or impossible to handle in batch reactors.
The economic benefits resulting from the technology are mainly due to the high yield and the low proportion of by-products, but also to the sustainable plant safety, lower energy consumption and a smaller carbon footprint.
And yet, MRT has not yet achieved the status in fine chemicals and active ingredient production that one might expect — at least not in Central Europe. What are the reasons for this? Five main topics emerged from the expert discussion: In addition to technology, the question of costs plays a decisive role, approval practice and know-how in the companies need to be improved, and entrepreneurship is needed for medium and long-term strategic decisions.

Well-proven Technology
“We are far beyond the lighthouse project phase,” emphasizes Christoph Hoever, who represents the Hoever Group and the company Quast, which builds microreactors: “We are in the implementation phase, in the phase of exploring many smaller laboratory facilities in order to see in which segments and in which areas micro reactor technology can actually be applied on a large scale today. ”
Bernhard Hettich, CTO of CHT Group, who has been using MRT in research and production for many years, agrees: “Today, every time a new product is developed, or a new process is introduced into production, we consider whether it can be done continuously. Nevertheless, it has not been widely accepted. Batch also has advantages, for example the flexibility of standardized reactor systems for a certain range of products.”
For Peter Pöchlauer of Thermo-Fisher Scientific, the use of MRT is part of their daily business, namely performing custom synthesis for pharmaceutical developers: “The question these companies ask is: How can I make appropriate amounts of the material of which I have made grams or milligrams in a library synthesis at the appropriate speed and in the appropriate quality? We have established a routine for this request: How do we want to do that? At which of our locations do we want to do that? Which production concept do we want to use? Do we want to do it in standard vessels? Do we want to develop a continuous manufactur­ing process? Or do we want to use a combination of continuous and discontin­uous process steps? Our goal is to make the right decision not only in the choice of chemicals, but also with regard to the production concept. We consider this as part of the normal procedure of a service operation.”
Joachim Heck, managing director of Ehrfeld Mikrotechnik, a company that markets micro- and milli reactors for usage from laboratory up to production, refers to a very successful large-scale technical application of MRT: “We have a shareholder from China who is now very successfully operating three production reactors, each with an annual production capacity of around 10,000 tons for an agro-active substance. The first of these reactors went into operation three years ago. Since then it has been running without any interruptions. It was only opened once after 6 months to demonstrate that no foul­ing occurred, a consequence of the significant high selectivities.
Summing up, Joerg Mohr, head of Process Development & Analytics at Saltigo, a Lanxess subsidiary in Leverkusen, Germany, confirms: “There are no fundamental obstacles: flow chemistry will continue to compete with conventional batch processes and offer an economically attractive and sustainable solution for suitable problems. The necessary tools are available. However, existing reference plants with their advantages should be made known more widely.” In summary, all participants of the roundtable discussion agreed: MRT is proven, reliable, and available.

Cost Considerations
In addition to the technical imperative to support the continuous improvement process through the use of technological progress, there is always the economic imperative in business practice: Cost and benefit must be in an economic balance.
This is also described by Andreas Haubrich from Sanofi in Frankfurt: “We develop continuous processes. In doing so, we look at complete syntheses. And if the building blocks such as selectivity, purity, safety that conti offers have a real benefit, then the process is carried out in conti. But at the top of the list is always the question: How does the process pay off? This is quite normal — also for me as a developer. When I present syntheses, when I work out a process for the production companies, I have to develop it in such a way that it can subsequently be implemented. And that‘s where cost pressure is quite normal.”
When a company must decide between investing in new continuous plant or continuing to operate batch equipment already depreciated, it can be difficult to introduce MRT. Comparing the production costs from this point of view, the batch process is almost always advantageous.
Joerg Mohr also emphasized this aspect: “One must basically differentiate between brownfield and greenfield projects. If I assume that I am going to build from scratch anyway, then I have other freedoms per se. In any case, the bottom line must be that it pays off. And if a new building is not economical, then there are no Conti plants. You can’t just realize one step of a multi-stage synthesis in conti mode, because then you would have to make the whole downstream process conti as well. As a consequence, the new process step, including purification and isolation, must be inte­grated into an overall solution that is suitable for the overall supply chain concept.”

Authorization Practice
Is there a connection between the construction of new plants in Germany and the authorization practice in our country? CHT manager Bernhard Hettich sees a particular problem here, regardless of the different federal states and production processes. With regard to MRT, he specified: “We all agree that downsized contin­uous processes are safer for various reasons, and that can be easily ex­plained even to non-experts. But we have not yet succeeded in making it clear to an authority that it should be easier to issue a license or obtain a permit for this technology. We are currently in the process of develop­ing a guideline for modular plants that not only favors large-scale chem­ical companies with their big sites, but also takes into account the requirements of medium-sized companies. This is an important task. We must exert political influence so that the new technologies, which undeniably have safety and environmental advantages, are recognized and correctly assessed by the decision-makers in regulatory organizations.”
Manfred Schrod, who has worked for various companies worldwide, has a similar view: “Not much has changed in the last 10 years with regard to approval procedures in Germany. The potential for microreactor technology probably lies outside Europe.”
All experts in the discussion group agree, that it should be much easier to obtain approval for a continuous plant with a smaller hold-up for hazardous substances than is currently the case.

Training, Know-how and Thinking in Pigeonholes
The experts also agree on this point: Education and training on the subject of conti and micro reaction technology needs to be improved. “In education, there is still far too much thinking in round bottom flasks”, said Bernhard Hettich, and Andreas Haubrich called for two equivalent options, which the chemist can use when planning a synthesis: “He needs two sets: one conti, one normal batch. And then he must know when to make use of which option. However, this is either taken into account too late or not at all during studies or training.”
Much of what goes from development to production is done in batches, because people don‘t know any other way. But then it is often too late due to lack of time to demonstrate and implement the advantages of a continuous process.
In addition to more intensive train­ing in higher education, a stronger emphasis on interdisciplinarity and multidisciplinarity is needed in operational practice. As Peter Pöchl­auer puts it: “The chemist must understand his process engineer and vice versa. And the process engineer must understand his plant engineer as well as his analytical chemist — and vice versa. And the plant engineer must understand what the opportunities are in an operational production. Therefore, this kind of multidisciplinarity is what I have to create in my company to be able to make successful developments.”
Joachim Heck emphasized that the corresponding training courses, whether in chemistry, chemical engineering or process engineering, are already providing systematic training on the topic of flow chemistry: “There are chairs, where work is being done on this topic, but not yet across the board. By no means every graduate, whether in chemistry or process engineering, has sound skills in continuous process technology.”
But the companies are also under an obligation: “Interdisciplinarity is also part of training. And we can promote interdisciplinarity in the companies by recruiting very different people and by regularly integrating them to different tasks and projects. The results are incredible”, emphasized Bernhard Hettich.

Sustainability and Entrepreneurship
The CHEMonitor survey, a market trend barometer conducted by CHEManager and Camelot Management Consulting, at the end of 2019 revealed a less than positive mood in the chemical industry, but also encouraged with statements such as “change is necessary, we need a recipe for the future. A change in values can remedy the situation!” With the statement: “Sustainability in the business model is one of the opportunities”, the question arises how MRT and flow chemistry can contribute to this, as this technology is particularly characterized by a higher material yield, lower energy input and higher purity of the starting material.
Evonik expert Michael Doludda confirmed: “Sustainability is one of Evonik’s top priorities. We are currently conducting massive carbon footprint studies and we are also involving all our suppliers in this process. As a Group, we also want to consider a sustainability factor, that is, an internal CO₂ price, when making investment decisions. This aspect should actually be an advantage for microreactor technology.”
“From CHT‘s point of view”, Bernhard Hettich said, “we have had a sustainability strategy based on three pillars for several years: economic, environmental and social — not just carbon footprint. And this is also our decision-making basis. But I would not say that flow chemistry is generally more sustainable. Of course, we have less hold-up of any substances that you don‘t want to have on a 10-ton scale. MRT is more economical when it comes to production costs or investment costs. And economically it is also more sustainable. To derive a direct link between carbon footprint and flow chemistry seems not to be obvious spontaneously. We do flow chemistry or microreaction technology because it offers advantages. And when we approach something new, we try to find out whether it offers advantages at the point where it is needed. Sometimes it does, but often it doesn‘t. And of course, we also see that many things work that don‘t work in batch or wouldn‘t have worked at all. These are great advantages.”
For Peter Pöchlauer, too, a key question for continuous process engineering is profitability: “How can I make MRT fit my business models particularly well?” Of course, the carbon footprint or process mass intensity, a key figure used by pharmacists, also plays a role. But above all, safety considerations are also very important: “When route scouting for a target molecule, not only the brevity or the effort is evaluated, but also the raw material consumption. And here, of course, one often sees that the most hazardous reagents, which nobody likes to touch, are very efficient. With all these considerations, a grip in the Conti drawer can be more advantageous.” His summary: “Flow Chemistry will continue to prevail to the extent that it can be shown to fit our business models, our ambitions in environmental protection and our ambitions as a reliable manufacturer of high-quality chemicals. This is where I see our advantage to the Far East markets. These three points mean that Flow Chemistry can make our chemical production in Europe sustainable. And that is what we really want. We have every opportunity to make chemical production in Europe sustainable.”
Christoph Hoever is confident: “In the long term, MRT will establish it­self because the sum of the advantages from the economic side, both in terms of raw material and energy savings and efficiency, is given. The possibility of upscaling from laboratory scale to smaller reactors up to large-scale production is another big advantage.”
Does this mean that there is a lack of willingness to make decisions and take risks, to try out new things? Anne Kaaden from Ehrfeld Mikrotechnik asked the question of entrepreneurial courage: “Is Germany or Europe overperforming? Do I always have to know my return on investment in detail before I enter a new technology? To consider too much details leads to a loss of time and that definitely leads to a loss of money.”
More entrepreneurial courage in flow chemistry can therefore bring new opportunities — especially because safety, sustainability and efficiency are inseparably linked to this technology. A continuously and successfully running reference project with a production capacity of thirty thousand tons of product per year proves the possibilities of MRT. Now it is up to the decision-makers in the chemical and pharmaceutical industry to take up the baton and break new ground for process technologies.